Project Summary Significance: The maturation of and connection among brain regions involved in emotion regulation and higher cognitive functioning during adolescence is hypothesized to render these regions sensitive to changes in the hormonal milieu. There is evidence from experimental animal and human studies that estrogen modulates neuronal function in a variety of brain areas including in the amygdala, hippocampus, striatum, and prefrontal cortex. These regions also are involved in the processing of emotional and hedonic stimuli. Thus, for many women ovarian hormones may be critical to the functional integrity of positive and negative valence systems. We propose to test associations between estrogen levels and individual differences in neural and behavioral response to reward and positive emotional stimuli and self-reported positive mood (positive valence system) and to loss and negative emotional stimuli and self-reported negative mood (negative valence system). Aims: 1) Test associations between estrogen and neural and behavioral response to stimuli that activate positive and negative valence systems; 2) Test whether earlier stress exposure, depression history, and pubertal timing and tempo moderate associations between estrogen and neural and behavioral response to stimuli that activate positive and negative valence systems. Approach: Urine samples are available for 150 late adolescent girls participating in a longitudinal study who have completed an fMRI assessment of response to emotional stimuli. Urine samples were collected immediately prior to the scanning session and then stored at -40. Data on exposure to stressors (e.g., negative family events, abuse, trauma), depression symptoms, and pubertal development were collected prospectively beginning in childhood and continuing through late adolescence. The goal of the present application is to assay the urine for an estrogen metabolite, and test the association between estrogen levels and individual differences in neural and behavioral response to positive/negative face emotion and reward/loss, as well as models of moderation. Investigators: Dr. Kathryn Keenan serves as the PI with Co-investigators Drs. C. Neill Epperson and Mary Jane De Souza, both of whom are experts in the interface of ovarian hormones, mood, and behavior, Dr. Erika Forbes, an expert in using fMRI to probe neural response to emotional stimuli in adolescents, and biostatistician, Kristen Wroblewski. Impact: The sample size would be one of the largest to date and will yield sufficient power for testing models of moderation. Hormone levels will be assessed directly and immediately prior to the assessment of functioning of positive and negative valence systems, thus obviating the significant limitation of inferring level from phase of cycle. Multimodal assessments of functioning are completed within each subject, providing an opportunity to test more refined models of how hormones impact psychological processes. The leveraging of the prospectively collected data from the parent grants provides an unprecedented opportunity to identify factors that may increase neural sensitivity to ovarian hormones, which will significantly extend the existing literature in this area. The results from the proposed study have the potential to impact clinical practice paradigms by specifying clinical targets within each of the two emotion systems, elucidating the role of mood in the physiological disturbance, and identifying a subgroup who may be particularly vulnerable to hormone related dysfunction in emotion systems.